The objective of this proposal is to determine how hyperthermia can be used most effectively in the treatment of cancer in combination with radiation through the use of hyperthermic sensitizer, a compound that would enhance greater killing of cancer cells by heat. Since several classes of drugs are shown to be both excellent hyperthermic sensitizer and radiosensitizer in cell culture studies, substantial therapeutic gain might be anticipated, if in vitro findings are to be confirmed with well defined in vivo tumors of specific sites. Experiments will be carried out with two in vivo tumor system. They are RIF-1 fibrosarcoma growing intramuscularly in C3H mice and 9L gliosarcoma growing intracerebrally in Fischer rats, both highly radio-resistant tumors. Two classes of drugs to be tested are (i) acidic pH thermosensitizer (lonidamine and gossypol) and (ii) hypoxic cell thermosensitizer (5-thio-D-glucose, rhodamine-123 and pentalenolactone). The initial studies will be directed to determine the optimum time and sequence of heat and drugs by measuring pharmacokinetics, pH and blood flow of tumor and normal tissues (skin and brain). The end points for tumor response will be tumor regrowth, tumor cure and single cell clonogenic assays. The second phase of study will be to determine thermosensitizer enhancement ratio of three way combined treatment of radiation, heat and drugs for tumor tissues. The final phase of the study will be to determine the normal tissue tolerance of both acute and late effects of the combined modality. Significance of the study will be to identify key radiobiological factors that would selectively improve therapeutic index of the combined heat and radiation in the treatment of radioresistant human tumors, such as soft tissue sarcoma and malignant brain tumors.